ApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition

DeMattos, Ronald B; Cirrito, John R; Parsadanian, Maia; May, Patrick C; O'Dell, Mark A; Taylor, Jennie W; Harmony, Judith A.K; Aronow, Bruce J; Bales, Kelly R; Paul, Steven M; Holtzman, David M

doi:10.1016/s0896-6273(03)00850-x

Cited by 459Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchClusterin in disease pathology

ApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition

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DeMattos, Ronald B, Cirrito, John R, Parsadanian, Maia, May, Patrick C, O'Dell, Mark A, Taylor, Jennie W, Harmony, Judith A.K, Aronow, Bruce J +3 more·2004·Neuron

DOI 10.1016/s0896-6273(03)00850-x

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Abstract

Apolipoprotein E (apoE) and clusterin can influence structure, toxicity, and accumulation of the amyloid-beta (Abeta) peptide in brain. Both molecules may also be involved in Abeta metabolism prior to its deposition. To assess this possibility, we compared PDAPP transgenic mice that develop age-dependent Abeta accumulation in the absence of apoE or clusterin as well as in the absence of both proteins. apoE(-/-) and clusterin(-/-) mice accumulated similar Abeta levels but much less fibrillar Abeta. In contrast, apoE(-/-)/clusterin(-/-) mice had both earlier onset and markedly increased Abeta and amyloid deposition. Both apoE(-/-) and apoE(-/-)/clusterin(-/-) mice had elevated CSF and brain interstitial fluid Abeta, as well as significant differences in the elimination half-life of interstitial fluid Abeta measured by in vivo microdialysis. These findings demonstrate additive effects of apoE and clusterin on influencing Abeta deposition and that apoE plays an important role in regulating extracellular CNS Abeta metabolism independent of Abeta synthesis.

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Changes in apoE and Aβ metabolism in the brain ISF early in life can markedly alter Aβ deposition later in life.
“Because changes in apoE and Aβ metabolism in the brain ISF early in life can markedly alter Aβ deposition later in life (31, 32)”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [32]
Mice lacking apoE have accelerated Aβ clearance from the brain relative to apoE-expressing mice.
“This idea is supported by the fact that mice lacking apoE have accelerated Aβ clearance from the brain relative to apoE-expressing mice (DeMattos et al., 2004).”
From Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis (2011) · cites this paper as DeMattos et al., 2004
ApoE regulates both extracellular and intracellular Aβ clearance in the brain.
“Furthermore, recent studies strongly suggest that apoE regulates both extracellular and intracellular Aβ clearance in the brain (Bell et al., 2007; Deane et al., 2008; DeMattos et al., 2004; Jiang et al., 2008).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as DeMattos et al., 2004
ApoE regulates Aβ clearance in the brain.
“Furthermore, apoE has been shown to regulate Aβ clearance in the brain (Bell et al., 2007; Deane et al., 2008; DeMattos et al., 2004; Jiang et al., 2008).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as DeMattos et al., 2004
ApoE decreases the elimination rate of soluble Aβ from the ISF.
“Given that LDLR overexpression did not appear to alter APP processing (Figure S3B), and based on our previous finding that apoE decreased the elimination rate of soluble Aβ from the ISF (DeMattos et al., 2004), we hypothesized that the lower steady state concentration of eAβ in APP/PS1/LDLR mice is likely the result of increased elimination from the brain ISF (Deane et al., 2008; DeMattos et al.,”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as DeMattos et al., 2004

It is likely that the reduction of apoE protein levels by LDLR overexpression enhanced Aβ clearance.
“Though it is likely that the reduction of apoE protein levels by LDLR overexpression enhanced Aβ clearance (DeMattos et al., 2004)”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as DeMattos et al., 2004
Mice lacking apoE have faster Aβ clearance relative to apoE-expressing mice.
“This possibility is supported by the fact that mice lacking apoE have faster Aβ clearance, relative to apoE-expressing mice (DeMattos et al., 2004).”
From Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis (2012) · cites this paper as DeMattos et al., 2004
Expression of apoE3 results in a dose-dependent decrease in amyloid burden.
“Conversely, expression of apoE3 results in a dose-dependent decrease in amyloid burden [95].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [95]
APOE regulates extracellular Aβ metabolism independently of Aβ synthesis, and APOE isoforms differentially influence the clearance of soluble Aβ from the brain.
“Indeed, APOE has been shown to regulate extracellular Aβ metabolism independently of Aβ synthesis, and APOE isoforms differentially influence the clearance of soluble Aβ from the brain (Castellano et al., 2011; DeMattos et al., 2004).”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as DeMattos et al., 2004
Endogenous CNS-derived apoE-containing lipoprotein particles bind to Aβ and promote its clearance and degradation.
“endogenous CNS-derived apoE-containing lipoprotein particles bind to A␤ and promote its clearance and degradation (DeMattos et al., 2004;Koistinaho et al., 2004;Manelli et al., 2004;Stratman et al., 2005;Trommer et al., 2005)”
From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as DeMattos et al., 2004
The result that lack of apoE may increase soluble Aβ levels in young PDAPP mice was also demonstrated in a study using in vivo microdialysis to analyze the level of Aβ in brain interstitial fluid.
“This result was also demonstrated in a study where in vivo microdialysis was used to analyze the level of Aβ in brain interstitial fluid (ISF) (DeMattos et al., 2004).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as DeMattos et al., 2004
CLU participates in Aβ clearance, principally of Aβ42, from the brain across the blood brain barrier.
“CLU, which is one of the most abundantly expressed apolipoproteins in the central nervous system (like ApoE) [106], participates in Aβ clearance, principally of the highly pathogenic Aβ42 peptide, from the brain across the BBB [24].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [24]
Clusterin levels are significantly lower in APOE knockout mice.
“Additionally, Western blotting revealed that CLU levels were significantly lower in APOE−/− mice (p=1×10−4) (DeMattos, et al., 2004) suggesting that there could be an interaction between CLU and APOE”
From A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin (2016) · cites this paper as DeMattos, et al., 2004
The effects of APOE and CLU on amyloid-beta levels are additive and not completely independent.
“APOE−/− and CLU−/− mice have similar Aβ levels, but in an APOE/CLU double knock-out mouse model Aβ was significantly increased in CSF and brain interstitial fluid, suggesting that the APOE and CLU effects on Aβ levels are additive and not completely independent (DeMattos, et al., 2004)”
From A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin (2016) · cites this paper as DeMattos, et al., 2004
Mice lacking both CLU and APOE have increased amyloid deposition and higher soluble and insoluble amyloid-beta 40 and 42 in CSF than mice lacking only one of these genes.
“A previous study demonstrated that CLU−/−/APOE−/− mice had increased amyloid deposition and significantly higher levels of soluble and insoluble Aβ40 and Aβ42 in the CSF (p<0.001) than CLU−/− or APOE−/− alone (DeMattos, et al., 2004)”
From A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin (2016) · cites this paper as DeMattos, et al., 2004
Both genetic and non-genetic risk factors for late-onset sporadic AD increase Aβ generation and/or reduce Aβ clearance for its accumulation.
“Both genetic (e.g., ApoE4, TREM2) and non-genetic (e.g. diabetes, obesity, stroke, or physical inactivity) risk factors for late-onset sporadic Alzheimer’s disease (SAD) have also been identified to increase Aβ generation and/or reduce Aβ clearance for its accumulation.4,41–45”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [41]

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Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459 · see citing works
Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease
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Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders
Zlokovic, B. V. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3114 · Cited by 2,969 · see citing works
Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease
the European Alzheimer's Disease Initiative Investigators, Lambert, J.-C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros, O., Zelenika, D., Bullido, M. J., et al. (2009) · Nature Genetics · doi:10.1038/ng.439 · Cited by 2,234 · see citing works
Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease
Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. (2010) · Science · doi:10.1126/science.1197623 · Cited by 2,078 · see citing works
Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935 · see citing works
“…molecules in the brain, is present in Aβ plaques (Namba et al., 1991; Wisniewski and Frangione, 1992; Zhan et al., 1995) and contributes to both the clearance and the amyloid deposition of Aβ peptide (Bales et al., 1997a; DeMattos et al., 2004; Bien-Ly et al., 2012; Holtzman et al., 2012).”
Alzheimer's disease
Masters, C. L., Bateman, R., Blennow, K., Rowe, C. C., Sperling, R. A., & Cummings, J. L. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.56 · Cited by 1,853 · see citing works
The role of apolipoprotein E in Alzheimer's disease
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Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
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Synaptic Activity Regulates Interstitial Fluid Amyloid-β Levels In Vivo
Cirrito, J. R., Yamada, K. A., Finn, M. B., Sloviter, R. S., Bales, K. R., May, P. C., Schoepp, D. D., Paul, S. M., Mennerick, S., & Holtzman, D. M. (2005) · Neuron · doi:10.1016/j.neuron.2005.10.028 · Cited by 1,265 · see citing works
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Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,227 · see citing works
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Deciphering the Molecular Basis of Memory Failure in Alzheimer's Disease
Walsh, D. M., & Selkoe, D. J. (2004) · Neuron · doi:10.1016/j.neuron.2004.09.010 · Cited by 1,207 · see citing works
Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
Bu, G. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2620 · Cited by 1,168 · see citing works
Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta
Griciuc, A., Serrano-Pozo, A., Parrado, A. R., Lesinski, A. N., Asselin, C. N., Mullin, K., Hooli, B., Choi, S. H., Hyman, B. T., & Tanzi, R. E. (2013) · Neuron · doi:10.1016/j.neuron.2013.04.014 · Cited by 1,004 · see citing works
TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia
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Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988 · see citing works
ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876 · see citing works
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The Genetics of Alzheimer Disease: Back to the Future
Bertram, L., Lill, C. M., & Tanzi, R. E. (2010) · Neuron · doi:10.1016/j.neuron.2010.10.013 · Cited by 834 · see citing works
APOE predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging
Morris, J. C., Roe, C. M., Xiong, C., Fagan, A. M., Goate, A. M., Holtzman, D. M., & Mintun, M. A. (2010) · Annals of Neurology · doi:10.1002/ana.21843 · Cited by 830 · see citing works
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Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease
Holtzman, D. M., Herz, J., & Bu, G. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006312 · Cited by 782 · see citing works
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apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain
Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M. B., Holtzman, D. M., & Zlokovic, B. V. (2008) · Journal of Clinical Investigation · doi:10.1172/jci36663 · Cited by 771 · see citing works
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History and progress of hypotheses and clinical trials for Alzheimer’s disease
Liu, P.-P., Xie, Y., Meng, X.-Y., & Kang, J.-S. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0063-8 · Cited by 723 · see citing works
P-glycoprotein deficiency at the blood-brain barrier increases amyloid- deposition in an Alzheimer disease mouse model
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ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
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Linking Aβ and Tau in Late-Onset Alzheimer's Disease: A Dual Pathway Hypothesis
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Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus
Xu, Q., Bernardo, A., Walker, D., Kanegawa, T., Mahley, R. W., & Huang, Y. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.5476-05.2006 · Cited by 524 · see citing works
Alzheimer’s Disease Genetics: From the Bench to the Clinic
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RAGE (Yin) Versus LRP (Yang) Balance Regulates Alzheimer Amyloid β-Peptide Clearance Through Transport Across the Blood–Brain Barrier
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Clusterin in Alzheimer’s Disease: Mechanisms, Genetics, and Lessons From Other Pathologies
Foster, E. M., Dangla-Valls, A., Lovestone, S., Ribe, E. M., & Buckley, N. J. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00164 · Cited by 381 · see citing works
Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease
Wahrle, S. E., Jiang, H., Parsadanian, M., Kim, J., Li, A., Knoten, A., Jain, S., Hirsch-Reinshagen, V., Wellington, C. L., Bales, K. R., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci33622 · Cited by 370 · see citing works
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IL-10 Alters Immunoproteostasis in APP Mice, Increasing Plaque Burden and Worsening Cognitive Behavior
Chakrabarty, P., Li, A., Ceballos-Diaz, C., Eddy, J. A., Funk, C. C., Moore, B., DiNunno, N., Rosario, A. M., Cruz, P. E., Verbeeck, C., et al. (2015) · Neuron · doi:10.1016/j.neuron.2014.11.020 · Cited by 354 · see citing works
Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels
Riddell, D. R., Zhou, H., Atchison, K., Warwick, H. K., Atkinson, P. J., Jefferson, J., Xu, L., Aschmies, S., Kirksey, Y., Hu, Y., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1972-08.2008 · Cited by 342 · see citing works
Expression of Novel Alzheimer’s Disease Risk Genes in Control and Alzheimer’s Disease Brains
Karch, C. M., Jeng, A. T., Nowotny, P., Cady, J., Cruchaga, C., & Goate, A. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0050976 · Cited by 328 · see citing works
Caloric restriction attenuates Aβ-deposition in Alzheimer transgenic models
Patel, N. V., Gordon, M. N., Connor, K. E., Good, R. A., Engelman, R. W., Mason, J., Morgan, D. G., Morgan, T. E., & Finch, C. E. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.09.014 · Cited by 329 · see citing works
Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid β Peptide
Hashimoto, T., Serrano-Pozo, A., Hori, Y., Adams, K. W., Takeda, S., Banerji, A. O., Mitani, A., Joyner, D., Thyssen, D. H., Bacskai, B. J., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.1542-12.2012 · Cited by 294 · see citing works
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Human Apolipoprotein E4 Alters the Amyloid-β 40:42 Ratio and Promotes the Formation of Cerebral Amyloid Angiopathy in an Amyloid Precursor Protein Transgenic Model
Fryer, J. D., Simmons, K., Parsadanian, M., Bales, K. R., Paul, S. M., Sullivan, P. M., & Holtzman, D. M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.5170-04.2005 · Cited by 278 · see citing works
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Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance
Kim, J., Castellano, J. M., Jiang, H., Basak, J. M., Parsadanian, M., Pham, V., Mason, S. M., Paul, S. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.11.013 · Cited by 274 · see citing works
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Astrocytic LRP1 Mediates Brain Aβ Clearance and Impacts Amyloid Deposition
Liu, C.-C., Hu, J., Zhao, N., Wang, J., Wang, N., Cirrito, J. R., Kanekiyo, T., Holtzman, D. M., & Bu, G. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.3442-16.2017 · Cited by 267 · see citing works
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Low‐density lipoprotein receptor‐related protein‐1: a serial clearance homeostatic mechanism controlling Alzheimer’s amyloid β‐peptide elimination from the brain
Zlokovic, B. V., Deane, R., Sagare, A. P., Bell, R. D., & Winkler, E. A. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.07002.x · Cited by 261 · see citing works
The LXR agonist TO901317 selectively lowers hippocampal Aβ42 and improves memory in the Tg2576 mouse model of Alzheimer's disease
Riddell, D. R., Zhou, H., Comery, T. A., Kouranova, E., Lo, C. F., Warwick, H. K., Ring, R. H., Kirksey, Y., Aschmies, S., Xu, J., et al. (2007) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2007.01.011 · Cited by 244 · see citing works
Neurovascular Dysfunction and Faulty Amyloid -Peptide Clearance in Alzheimer Disease
Sagare, A. P., Bell, R. D., & Zlokovic, B. V. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a011452 · Cited by 251 · see citing works
Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests
Bates, K. A., Verdile, G., Li, Q.-X., Ames, D., Hudson, P., Masters, C. L., & Martins, R. N. (2009) · Molecular Psychiatry · doi:10.1038/mp.2008.96 · Cited by 247 · see citing works
The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease
Hirsch-Reinshagen, V., Maia, L. F., Burgess, B. L., Blain, J.-F., Naus, K. E., McIsaac, S. A., Parkinson, P. F., Chan, J. Y., Tansley, G. H., Hayden, M. R., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508781200 · Cited by 233 · see citing works
Untangling Genetic Risk for Alzheimer’s Disease
Pimenova, A. A., Raj, T., & Goate, A. M. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.05.014 · Cited by 223 · see citing works
Plasma clusterin and the risk of Alzheimer disease
Schrijvers, E. M. C. (2011) · JAMA · doi:10.1001/jama.2011.381 · Cited by 220 · see citing works
APOE and Alzheimer’s Disease: Evidence Mounts that Targeting APOE4 may Combat Alzheimer’s Pathogenesis
Uddin, M. S., Kabir, M. T., Al Mamun, A., Abdel-Daim, M. M., Barreto, G. E., & Ashraf, G. M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1237-z · Cited by 212 · see citing works
Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins
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Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer’s Disease
Kirouac, L., Rajic, A. J., Cribbs, D. H., & Padmanabhan, J. (2017) · eneuro · doi:10.1523/eneuro.0149-16.2017 · Cited by 207 · see citing works
Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis
Kim, J., Jiang, H., Park, S., Eltorai, A. E. M., Stewart, F. R., Yoon, H., Basak, J. M., Finn, M. B., & Holtzman, D. M. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3773-11.2011 · Cited by 199 · see citing works
“This idea is supported by the fact that mice lacking apoE have accelerated A clearance from the brain relative to apoE-expressing mice (DeMattos et al., 2004).”
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Low-density Lipoprotein Receptor Represents an Apolipoprotein E-independent Pathway of Aβ Uptake and Degradation by Astrocytes
Basak, J. M., Verghese, P. B., Yoon, H., Kim, J., & Holtzman, D. M. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.288746 · Cited by 192 · see citing works
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Lipid Alterations in the Earliest Clinically Recognizable Stage of Alzheimers Disease: Implication of the Role of Lipids in the Pathogenesis of Alzheimers Disease
Han, X. (2005) · Current Alzheimer Research · doi:10.2174/1567205052772786 · Cited by 183 · see citing works
Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia
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The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis?
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Wnts in adult brain: from synaptic plasticity to cognitive deficiencies
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Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice
Hu, J., Liu, C.-C., Chen, X.-F., Zhang, Y.-W., Xu, H., & Bu, G. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0001-3 · Cited by 161 · see citing works
Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis
Kim, J., Eltorai, A. E. M., Jiang, H., Liao, F., Verghese, P. B., Kim, J., Stewart, F. R., Basak, J. M., & Holtzman, D. M. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20121274 · Cited by 160 · see citing works
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Plasma levels of apolipoprotein <scp>E</scp> and risk of dementia in the general population
Rasmussen, K. L., Tybjærg‐Hansen, A., Nordestgaard, B. G., & Frikke‐Schmidt, R. (2015) · Annals of Neurology · doi:10.1002/ana.24326 · Cited by 156 · see citing works
Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis
Castellano, J. M., Deane, R., Gottesdiener, A. J., Verghese, P. B., Stewart, F. R., West, T., Paoletti, A. C., Kasper, T. R., DeMattos, R. B., Zlokovic, B. V., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206446109 · Cited by 154 · see citing works
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Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity
Wilson, M. R., Yerbury, J. J., & Poon, S. (2007) · Molecular BioSystems · doi:10.1039/b712728f · Cited by 142 · see citing works
Neurotheranostics as Personalized Medicines
Kevadiya, B. D., Ottemann, B. M., Thomas, M. B., Mukadam, I., Nigam, S., McMillan, J., Gorantla, S., Bronich, T. K., Edagwa, B., & Gendelman, H. E. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.10.011 · Cited by 124 · see citing works
Apolipoprotein E and Low Density Lipoprotein Receptor-related Protein Facilitate Intraneuronal Aβ42 Accumulation in Amyloid Model Mice
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Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review
Rasmussen, K. L. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.10.037 · Cited by 125 · see citing works
Genome-wide significant risk factors for Alzheimer’s disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment
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Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis
Kaji, S., Berghoff, S. A., Spieth, L., Schlaphoff, L., Sasmita, A. O., Vitale, S., Büschgens, L., Kedia, S., Zirngibl, M., Nazarenko, T., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.09.014 · Cited by 104 · see citing works
Identification of Alzheimer's disease–associated long noncoding RNAs
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Oxidative signature of cerebrospinal fluid from mild cognitive impairment and Alzheimer disease patients
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Ablation of reactive astrocytes exacerbates disease pathology in a model of Alzheimer's disease
Katsouri, L., Birch, A. M., Renziehausen, A. W. J., Zach, C., Aman, Y., Steeds, H., Bonsu, A., Palmer, E. O. C., Mirzaei, N., Ries, M., et al. (2020) · Glia · doi:10.1002/glia.23759 · Cited by 81 · see citing works
Hepatic soluble epoxide hydrolase activity regulates cerebral Aβ metabolism and the pathogenesis of Alzheimer’s disease in mice
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A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin
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“A previous study demonstrated that CLU / /APOE / mice had increased amyloid deposition and significantly higher levels of soluble and insoluble Ab40 and Ab42 in the CSF (p 0.001) than CLU / or APOE / alone (DeMattos et al., 2004).”
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Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer’s disease
Eteleeb, A. M., Novotny, B. C., Tarraga, C. S., Sohn, C., Dhungel, E., Brase, L., Nallapu, A., Buss, J., Farias, F., Bergmann, K., et al. (2024) · PLOS Biology · doi:10.1371/journal.pbio.3002607 · Cited by 64 · see citing works
Apolipoprotein J (clusterin) activates rodent microglia in vivo and in vitro
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Immunohistochemical analysis of transporters related to clearance of amyloid-β peptides through blood–cerebrospinal fluid barrier in human brain
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Amyloid-β and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus
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Genetic perturbations of disease risk genes in mice capture transcriptomic signatures of late-onset Alzheimer’s disease
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Authors: DeMattos, R. B., Cirrito, J. R., Parsadanian, M., May, P. C., O'Dell, M. A., Taylor, J. W., Harmony, J. A. K., Aronow, B. J., Bales, K. R., Paul, S. M., & Holtzman, D. M.
Affiliations: Eli Lilly (United States) (US)
Washington University in St. Louis (US)
University of Cincinnati (US)
Cincinnati Children's Hospital Medical Center (US)
Corresponding author: DeMattos, Ronald B
Holtzman, David M
ORCID: DeMattos, Ronald B
Cirrito, John R
May, Patrick C
Taylor, Jennie W
Aronow, Bruce J
Paul, Steven M
Holtzman, David M
Venue: Neuron
Publisher: Elsevier BV
Published: 2004-01
Volume: 41
Issue: 2
Pages: 193-202
ISSN: 0896-6273 (ISSN-L)
DOI: 10.1016/s0896-6273(03)00850-x
OpenAlex: W1966874118
Cited by: 459
References: 59
Citations by year: 2026: 10 · 2025: 11 · 2024: 21 · 2023: 22 · 2022: 14 · 2021: 15 · 2020: 28 · 2019: 23 · 2018: 17 · 2017: 17 · 2016: 21 · 2015: 23 · 2014: 30 · 2013: 23 · 2012: 32
FWCI: 14.22
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 3485 d)
Locations: Neuron (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (AG11355, AG 05681, P50AG005681, AG13956, P01AG011355)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Health Sciences › Medicine › Oncology › Clusterin in disease pathology
Keywords: apolipoprotein E, clusterin, amyloid-beta, amyloid-beta deposition, amyloid-beta metabolism, fibrillar amyloid-beta, cerebrospinal fluid amyloid-beta, Alzheimer's disease, knockout mice
MeSH terms: Animals, Apolipoproteins E, Brain Chemistry, Extracellular Space, Genotype, Glycoproteins, Half-Life, Histocytochemistry, Blotting, Western, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microdialysis, Mice, Knockout, Molecular Chaperones, Clusterin, Mice

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ApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition

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